CD4+ Foxp3+ T regulatory (Treg) cells are essential for immune tolerance. It is now appreciated that signaling through IL2R is mandatory for Treg cells. During the last grant period we uncovered additional complexity by which IL2R signaling regulates Treg cells. By producing mice that selectively expressed mutations in signaling subdomains of IL2R&#946; in T lineage cells, natural Treg (nTreg) thymic development and peripheral homeostasis in vivo was shown to require minimal and transient IL2Rdependent Stat5 activation. More extensive IL2R signaling is required for the production of induced Treg (iTreg) cells in vitro and for tissue homing CD103+ and Klrg1+ nTreg subsets in vivo. Despite this progress, there remains a rudimentary understanding concerning how weak IL2R signaling controls Treg cell homeostasis and more extensive signaling regulates the function and development of peripheral nTreg subsets. In addition, the extent that production of iTreg cells in vivo depends upon IL2 is not known. We hypothesize that the IL2dependent mechanisms operating in the periphery controlling Treg homeostasis vs. nTreg and iTreg development are distinct. Therefore, one main objective is to define the cellular processes and pathways controlled by IL2 in peripheral Treg cells. Th17 effector cells are implicated in exacerbating several autoimmune diseases. As IL2 signaling diminishes, Th17 development increases and this represents an additional risk for autoimmunity. Considerable plasticity has been noted for the Th17 and iTreg cell fate choices and suggestive data implicate IL2 in Treg lineage stability. We hypothesize that it is the composite of IL2 activity on Treg vs. Th17 that predicts tolerance vs. autoimmunity and may in part be related to a role for IL2 in Treg lineage stability. Thus, other related objectives are to investigate the role of IL2 in Treg and Th17 cells and to relate these activities to susceptibility to autoimmune disease. The Specific Aims are: 1) To examine the extent varied IL2R signaling distinctively controls the homeostasis and development of Treg subsets&#894; 2) To evaluate the relationship of IL2Rdependent Treg and Th17 function in promoting and preventing autoimmune disease, including control of Treg lineage stability&#894; and 3) To establish the lineage interrelationship and functional relevance of CD103+ and Klrg1+ Treg subsets.